WO2017026386A1 - Patch - Google Patents

Abstract

The present invention addresses the problem of providing a patch that has a practical adhesiveness and cohesive force for medicinal use and provides an immediate anesthetic effect. Provided is a patch formed of an adhesive layer, said adhesive layer containing a mixture of lidocaine with another local anesthetic in an amount of 5 wt% or more and less than 20 wt%, wherein the adhesive layer contains at least a rubber-based adhesive and liquid paraffin and the content of a tackifier in the adhesive layer is not more than 10 wt%.

Description

Patch

The present invention relates to a patch that can be used for local anesthesia.

A local anesthetic preparation, which is a kind of transdermal absorption preparation, is widely used for the purpose of reducing pain caused during medical procedures such as venous needle puncture and minor skin surgery. As such a local anesthetic preparation, a lidocaine tape (Penless (registered trademark)) is commercially available in Japan. This tape preparation is a preparation (60% concentration) containing lidocaine crystals in an acrylic adhesive, and according to the attached document of this tape preparation, when used for pain relief at the time of puncture of an indwelling needle, It is described that it is applied to the site for about 30 minutes. However, in order to obtain a sufficient pain relieving effect, there is a report that an application time of 100 minutes is required on average (Non-patent Document 1). Due to problems, there is a demand for shortening the onset time of the anesthetic effect.

On the other hand, as a percutaneous absorption preparation for local anesthesia, a mixture containing two kinds of local anesthetics such as a mixture of lidocaine and prilocaine and a mixture of lidocaine and tetracaine has been proposed and administered as a single agent. It is known that it exhibits an excellent local anesthetic effect compared with the case where it was done. Actually, a cream preparation (Emra cream) obtained by emulsifying a mixture of lidocaine and prilocaine in an oil-in-water type is commercially available, and a higher anesthetic action has been confirmed than a cream preparation containing lidocaine alone or prilocaine alone (patented) Reference 1). However, in order to obtain a sufficient pain relieving effect using this cream, it is necessary to spread the cream so that it thickly swells on the skin, and to further use a closed closure (ODT) using a film or the like. There was a problem of becoming complicated.

Therefore, a simple tape preparation using a mixture of lidocaine and prilocaine as a drug has been proposed (Patent Document 2). Patent Document 2 discloses a prescription using a cross-linked acrylic pressure-sensitive adhesive, and an immediate effect of anesthesia is recognized as compared with a prior lidocaine tape (Penless (registered trademark)). However, according to the study by the present inventors, the skin permeability (in 薬 物 vitro test) of a drug that is an index of drug efficacy does not reach that of the previous cream, and is about twice that of Penless (registered trademark). It became clear that.

In addition, as a local anesthetic, a water-soluble patch composed of a mixture of lidocaine and prilocaine, a mixture of lidocaine and tetracaine, etc. has been proposed (Patent Document 3). There are problems such as low stickiness compared to water-insoluble tapes and easy removal from the skin.

Shingles is a disease accompanied by pain caused by the eruption caused by chickenpox and herpes zoster virus infection, which occurs along the skin segment of the nerve control area. Most herpes zoster patients lose their pain as the rash is healed, but some patients transition to postherpetic neuralgia where the pain remains even after the rash has healed. Postherpetic neuralgia is caused by damage or degeneration of peripheral nerve fibers caused by infected chickenpox and herpes zoster virus, and is classified as neuropathic pain. Since unbearable pain symptoms such as electric shock and allodynia that are rarely experienced in daily life occur continuously, the QOL of postherpetic neuralgia patients is significantly reduced. Regarding the aforementioned water-soluble patch, Liderderm (Lidocaine 5% Pap formulation, Endo Pharmaceuticals, Inc.) has been marketed in the United States as a therapeutic agent for postherpetic neuralgia. It is the first-line drug for neuropathic pain confined to sex. However, taking into account the long application time of 12 hours, there is always a risk of dropout due to its weak adhesive strength, and it is fully considered that the original therapeutic effect cannot be obtained due to dropout. Moreover, since the therapeutic effect of Lidoderm is not necessarily high (nonpatent literature 2), the patch which has a higher post-herpetic neuralgia therapeutic effect is calculated | required.

Japanese Patent Laid-Open No. 54-101414 JP 2010-22212 A JP 2013-116861 A

YAKUGAKU ZASSHI 127 (11) 1797-1799 (2007) PAIN 150 (3), 573-581 (2010)

An object of the present invention is to provide a patch having a practical adhesive force and a cohesive force as a pharmaceutical product and exhibiting a fast-acting anesthetic action.

As a result of intensive studies to solve the above problems, the present inventors have included, as a drug, "lidocaine and other local anesthetics" in a rubber-based adhesive layer having a tackifier of 10% by weight or less. It was clarified that a patch with extremely excellent drug skin permeability could be realized. Usually, when a rubber-based pressure-sensitive adhesive is used, it is difficult to realize a preparation having sufficient adhesive strength as a pharmaceutical if the content of the tackifier is small. Surprisingly, however, the present inventors have found that "mixture of lidocaine and other local anesthetics" contributes to maintaining and improving the adhesive strength, and thereby the adhesive strength and cohesive strength of the preparation are sufficiently high. A fast-acting local anesthetic preparation was completed. That is, the gist of the invention is as follows.

(1) A patch formed from an adhesive layer containing 5% by weight or more and less than 20% by weight of a mixture of lidocaine and another local anesthetic, wherein at least a rubber adhesive and liquid paraffin are contained in the adhesive layer A patch containing and containing 10% by weight or less of a tackifier in the adhesive layer.
(2) The patch according to (1), wherein the liquid paraffin is 0.5 to 2.6 times the weight of the rubber adhesive.
(3) The patch according to (1), wherein the liquid paraffin is 0.6 to 2.0 times by weight with respect to the rubber-based adhesive.
(4) The patch according to (1), wherein the liquid paraffin is 0.7 to 1.5 times the weight of the rubber-based adhesive.
(5) The patch according to any one of (1) to (4), wherein the rubber-based pressure-sensitive adhesive is a styrene-based block copolymer.
(6) The adhesive patch according to (5), wherein the rubber adhesive is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer.
(7) The content of the styrene-isoprene-styrene copolymer in the mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer is 15% by weight or more and 60% by weight or less. Patch.
(8) The content of the styrene-isoprene-styrene copolymer in the mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer is 20% by weight or more and 50% by weight or less. Patch.

(9) The patch according to (1), wherein the liquid paraffin is 2.0 to 6.0 times by weight with respect to the rubber-based adhesive.
(10) The patch according to (1), wherein the liquid paraffin is 2.3 to 5.5 times the weight of the rubber-based adhesive.
(11) The patch according to (1), wherein the liquid paraffin is 2.6 to 5.0 times by weight with respect to the rubber-based adhesive.
(12) The patch according to any one of (9) to (11), wherein the rubber adhesive is a styrene block copolymer.
(13) The adhesive patch according to (12), wherein the rubber adhesive is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer.
(14) The content of the styrene-isoprene-styrene copolymer in the mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer is 60% by weight or more and 95% by weight or less. Patch.
(15) The content of the styrene-isoprene-styrene copolymer in the mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer is 70% by weight or more and 90% by weight or less. Patch.

(16) The rubber adhesive is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer, the weight of liquid paraffin relative to the weight of the rubber adhesive is y, and the styrene-isoprene-styrene block. When the weight% of the styrene-isoprene-styrene copolymer in the mixture of the copolymer and the styrene-isoprene block copolymer is x and the base of the natural logarithm is e, 0.48e ^{0.022x -0.4≤y} The patch according to (1), which is represented by an exponential function of ≦ e ^0.021x +0.4.
(17) The rubber adhesive is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer, the weight of liquid paraffin relative to the weight of the rubber adhesive is y, and the styrene-isoprene-styrene block. When the weight% of the styrene-isoprene-styrene copolymer in the mixture of the copolymer and the styrene-isoprene block copolymer is x and the base of the natural logarithm is e, 0.48e ^{0.022x -0.2≤y} The patch according to (1), which is represented by an exponential function of ≦ e ^0.021x +0.2.
(18) The rubber adhesive is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer, the weight of liquid paraffin relative to the weight of the rubber adhesive is y, and the styrene-isoprene-styrene block. 0.48e ^0.022x ≤ y ≤ e ^0.021x , where x is the weight percent of the styrene-isoprene-styrene copolymer in the mixture of the copolymer and styrene-isoprene block copolymer and x is the base of the natural logarithm. The patch according to (1), which is represented by an exponential function of

(19) The patch according to any one of (1) to (18), wherein the other local anesthetic is prilocaine, tetracaine, or benzocaine.
(20) The patch according to (19), wherein the lidocaine content in the mixture of lidocaine and another local anesthetic is 30% by weight to 70% by weight.
(21) The patch according to (19), wherein the lidocaine content in the mixture of lidocaine and another local anesthetic is 40% by weight to 60% by weight.
(22) The patch according to (19), wherein the lidocaine content in the mixture of lidocaine and another local anesthetic is 45% by weight or more and 55% by weight or less.
(23) The patch according to (19), wherein the weight ratio of the mixture of lidocaine and another local anesthetic is 50/50.
(24) The patch according to any one of (19) to (23), wherein the content of the mixture of lidocaine and another local anesthetic is 5% by weight or more and less than 15% by weight with respect to the total amount of the adhesive component .
(25) The patch according to any one of (1) to (24), wherein the adhesive layer does not contain a tackifier.

(26) The patch according to any one of (1) to (25), which is used as a local anesthetic.
(27) The patch according to any one of (1) to (26), which is used as an analgesic or a pain treatment agent.
(28) The patch according to (27), which is used as a therapeutic agent for neuropathic pain.
(29) The patch according to (27), which is used as a therapeutic agent for postherpetic neuralgia.

(30) A method for local anesthesia comprising the step of applying the patch according to any one of (1) to (29) to an affected area of a patient requiring local anesthesia.
(31) A method for analgesia or pain treatment comprising the step of applying the patch according to any one of (1) to (29) to an affected area of a patient in need of analgesia or pain treatment.
(32) The method according to (31), wherein the pain is neuropathic pain.
(33) The method according to (31), wherein the pain is postherpetic neuralgia.

(34) Use of the patch according to any one of (1) to (29) for the production of a local anesthetic.
(35) Use of the patch according to any one of (1) to (29) for the manufacture of an analgesic or a pain therapeutic agent.
(36) The use according to (35), wherein the pain therapeutic agent is a neuropathic pain therapeutic agent.
(37) The use according to (35), wherein the pain therapeutic agent is a therapeutic agent for postherpetic neuralgia.

According to the present invention, it is possible to provide a patch for local anesthesia capable of realizing a rapid effect of an anesthetic effect.

FIG. 1 shows the measurement results of the cumulative drug skin permeation amount in the evaluation of in vitro rat skin permeability. FIG. 2 shows the measurement results of the drug skin permeation rate in the evaluation of in vitro rat skin permeability.

Hereinafter, the present invention will be described in detail. The patch of the present invention preferably has a support and at least one pressure-sensitive adhesive layer provided on the support.

The pressure-sensitive adhesive layer in the present invention contains (a) a mixture of lidocaine and another local anesthetic as a drug, and further contains (b) a rubber-based pressure-sensitive adhesive and (c) liquid paraffin.

(A) Lidocaine and other local anesthetic mixture The lidocaine that can be used in the present invention may be free lidocaine or a pharmaceutically acceptable salt of lidocaine. The pharmaceutically acceptable salt is not particularly limited, and may be an inorganic salt or an organic salt. Examples of inorganic salts of lidocaine include hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc., and examples of organic acid salts include formate, acetate, trifluoroacetate, propionic acid. Salt, lactate, tartrate, oxalate, fumarate, maleate, citrate, malonate, methanesulfonate and the like can be mentioned. From the viewpoint of availability, free lidocaine or lidocaine hydrochloride is preferably used, and from the viewpoint of dispersibility in the pressure-sensitive adhesive, it is particularly preferable to use free lidocaine.

Other local anesthetics that can be used in the present invention have a basic skeleton composed of an aromatic ring, an alkyl chain, and an amino group, and have a structure in which the aromatic ring and the alkyl chain are connected by an ester bond or an amide bond. If it is, it will not specifically limit. Examples of such other local anesthetics include prilocaine, tetracaine, benzocaine, bupivacaine, mepivacaine and the like. The other local anesthetics described above exist in a solid state at room temperature, but a local anesthetic agent that decreases in melting point and is liquefied at room temperature when mixed with solid lidocaine can be preferably used.

Preferred as a mixture of lidocaine and other local anesthetics is a mixture of lidocaine-prilocaine, a mixture of lidocaine-tetracaine, a mixture of lidocaine-benzocaine, more preferably a mixture of lidocaine-prilocaine, a mixture of lidocaine-tetracaine. is there.

The lidocaine content in the mixture of lidocaine and other local anesthetics is preferably 30% by weight to 70% by weight, more preferably 40% by weight to 60% by weight, and even more preferably 45% by weight to 55% by weight. Most preferably, the weight ratio of the mixture of lidocaine and other local anesthetic is 50/50.

The lidocaine content in the lidocaine-prilocaine mixture is preferably 30% by weight to 70% by weight, more preferably 40% by weight to 60% by weight, and even more preferably 45% by weight to 55% by weight. In particular, since the melting point reduction is maximized by mixing at an equal weight ratio, the mixture is most preferably lidocaine / prilocaine = 50/50 (weight ratio).

The lidocaine content in the lidocaine-tetracaine mixture is preferably 30% by weight to 70% by weight, more preferably 40% by weight to 60% by weight, and even more preferably 45% by weight to 55% by weight. Most preferred is a mixture of lidocaine / tetracaine = 50/50 (weight ratio).

The lidocaine content in the mixture of lidocaine-benzocaine is preferably 20% by weight to 70% by weight, more preferably 30% by weight to 70% by weight, and may be 40% by weight to 60% by weight, or 45% by weight or more. It may be 55% by weight or less. Most preferred is a mixture of lidocaine / benzocaine = 30/70 (weight ratio).

The prilocaine that can be used in the present invention may be a free prilocaine or a pharmaceutically acceptable prilocaine salt. The pharmaceutically acceptable salt is not particularly limited, and examples thereof include the salts described for lidocaine. From the viewpoint of easy availability, it is preferable to use free-form prilocaine or prilocaine hydrochloride, and from the viewpoint of dispersibility in the pressure-sensitive adhesive, it is particularly preferable to use free-form prilocaine.

The tetracaine that can be used in the present invention may be free tetracaine or a pharmaceutically acceptable tetracaine salt. The pharmaceutically acceptable salt is not particularly limited, and examples thereof include the salts described for lidocaine. From the viewpoint of easy availability, it is preferable to use free tetracaine or tetracaine hydrochloride, and it is particularly preferable to use free tetracaine from the viewpoint of dispersibility in the pressure-sensitive adhesive.

The benzocaine that can be used in the present invention may be a free benzocaine or a pharmaceutically acceptable salt of benzocaine. The pharmaceutically acceptable salt is not particularly limited, and examples thereof include the salts described for lidocaine. From the viewpoint of easy availability, it is preferable to use free benzocaine or benzocaine hydrochloride, and it is particularly preferable to use free benzocaine from the viewpoint of dispersibility in an adhesive.

) By blending a mixture of lidocaine and other local anesthetics with a rubber-based adhesive, sufficient tackiness can be obtained at least as a pharmaceutical product.

The blending amount of lidocaine and other local anesthetics is preferably 5% by weight or more based on the total amount of the pressure-sensitive adhesive component in order to obtain sufficient medicinal effects. More preferably, it is 7 weight% or more. On the other hand, from the viewpoint of ensuring cohesive strength, the upper limit is preferably less than 20% by weight. More preferably, it is less than 15 weight%, More preferably, it is less than 12 weight%, Most preferably, it is 10 weight% or less. In the present specification, “adhesive component” means a component constituting the adhesive layer. The total amount of the pressure-sensitive adhesive component refers to the whole preparation excluding the support and the liner.

Among the above, the blending amount of lidocaine and another local anesthetic is preferably 5% by weight or more and less than 20% by weight, more preferably 5% by weight or more and less than 15% by weight, and particularly preferably 5% by weight. % By weight or more and less than 12% by weight, most preferably 7% by weight or more and less than 12% by weight.

(B) Rubber-based adhesive The rubber-based adhesive that can be used in the patch of the present invention is not particularly limited, and examples thereof include styrene-based block copolymers, polyisobutylene, natural rubber, butyl rubber, polyisoprene, and polybutene. Can be mentioned.

In particular, a styrene block copolymer is particularly preferable from the viewpoint of satisfying sufficient drug release properties, cohesiveness and adhesiveness, which are the objects of the present invention. Specific examples of styrene block copolymers include styrene-butadiene block copolymers, styrene-butadiene-styrene block copolymers, styrene-isoprene block copolymers, styrene-isoprene-styrene block copolymers, and styrene. -Ethylene / butylene block copolymer, styrene-ethylene / butylene-styrene block copolymer, styrene-ethylene / propylene block copolymer, styrene-ethylene / propylene-styrene block copolymer, styrene-isobutylene block copolymer And styrene-isobutylene-styrene block copolymer. In the above, “ethylene / butylene” represents a copolymer block of ethylene and butylene, and “ethylene / propylene” represents a copolymer block of ethylene and propylene. These styrenic block copolymers may be used alone or in combination of two or more.

Of the styrene block copolymers, one or two selected from the group consisting of styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers are preferably used from the viewpoint of availability. Particularly preferred is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer.

In an example of the present invention, when the mixing ratio of the styrene-isoprene block copolymer to the styrene-isoprene-styrene copolymer is low, the adhesiveness to the skin tends to decrease, and when it is high, the shape maintaining property of the adhesive layer is decreased. In some cases, such as a tendency to become.

In an example of the present invention, in the mixture of styrene-isoprene-styrene block copolymer and styrene-isoprene block copolymer, the upper limit of the styrene-isoprene-styrene block copolymer is preferably 95% by weight or less, and 90% by weight. % Or less, 80% by weight or less, 60% by weight or less, or 50% by weight or less. The lower limit is preferably 10% by weight or more, 15% by weight or more, 20% by weight or more, 50% by weight or more, 60% by weight or more, or 70% by weight or more.

In an example of the present invention, preferably, the content of the styrene-isoprene-styrene block copolymer in the mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene copolymer is 10% by weight or more and 90% by weight or less. More preferably 15 to 60% by weight, most preferably 20 to 50% by weight.

In another example of the present invention, the styrene-isoprene-styrene block copolymer content in the mixture of styrene-isoprene-styrene block copolymer and styrene-isoprene copolymer is preferably 50 wt% or more and 95 wt%. Or less, more preferably 60% by weight or more and 95% by weight or less, and most preferably 70% by weight or more and 90% by weight or less.

The styrene content in the styrene-isoprene-styrene block copolymer and styrene-isoprene copolymer is not particularly limited, but the lower limit of the styrene content is preferably 5% by weight or more, particularly preferably 10% by weight or more. The upper limit of the styrene content is preferably 50% by weight or less, more preferably 30% by weight or less, and most preferably 20% by weight or less.

The styrene content in the styrene-isoprene-styrene block copolymer and styrene-isoprene copolymer is preferably 5% by weight to 50% by weight, more preferably 10% by weight to 30% by weight, among the above. Or less, and most preferably 10 wt% or more and 20 wt% or less.

As the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer, a copolymer produced by a known method can be used, respectively, or a commercially available product satisfying the above characteristics can be used. wear. Also, a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer is commercially available. For example, “KRATON D1161”, “KRATON D1163”, “KRATON D1113”, “KRATON D1113”, “KRATON POLYMERS” KRATON D1119 ”,“ JSR 5229 ”,“ JSR 5403 ”,“ JSR 5505 ”manufactured by JSR Corporation,“ Quinac 3620 ”,“ Quintac 3421 ”,“ Quintac 3520 ”manufactured by Zeon Corporation.

The content of the rubber-based pressure-sensitive adhesive is not particularly limited as long as it does not impair the sufficient drug release property, cohesiveness, and pressure-sensitive adhesiveness, which are the objects of the present invention. In one example of the present invention, the lower limit of the rubber-based pressure-sensitive adhesive is preferably 15% by weight or more, more preferably 25% by weight or more, particularly preferably 30% by weight or more, based on the total amount of the pressure-sensitive adhesive component. Most preferably, it is 35 weight% or more. The upper limit of the rubber-based pressure-sensitive adhesive is preferably 60% by weight or less, more preferably 55% by weight or less, and most preferably 50% by weight or less based on the total amount of the pressure-sensitive adhesive component.

In one example of the present invention, the content of the rubber-based pressure-sensitive adhesive is preferably in the range of 30% by weight to 55% by weight, and more preferably in the range of 35% by weight to 50% by weight.

(C) Liquid paraffin Although the liquid paraffin which can be used by this invention is not specifically limited, A commercially available thing can be used suitably.

The liquid paraffin content used in the present invention is not particularly limited as long as it does not impair the effects of the present invention such as the pressure-sensitive adhesive and drug release properties. It is preferably 0.5 times or more, 0.6 times or more, 0.7 times or more, 0.8 times or more, 0.9 times or more, or 1. It may be 0 times or more, 1.5 times or more, 2.0 or more times, 2.3 or more times, or 2.6 or more times. The upper limit of the liquid paraffin is preferably 7.0 times by weight or less, 6.0 times by weight or less, 5.5 times by weight or less, and 5.0 weight by weight with respect to the rubber-based adhesive. 2 times or less, 3.0 times by weight or less, 2.6 times by weight or less, 2.0 times by weight or less, 1.7 times by weight or less, 1.6 times by weight or less, It may be 1.5 times or less.

In one example, the liquid paraffin content is preferably 0.5 to 2.6 times by weight, more preferably 0.6 to 2.0 times by weight with respect to the rubber-based pressure-sensitive adhesive. Or less, more preferably 0.7 to 1.7 times, particularly preferably 0.7 to 1.6 times, most preferably 0.7 to 1 times. .5 weight times or less.

In another example, the liquid paraffin content is preferably 2.0 times by weight or more and 6.0 times by weight or less, more preferably 2.3 times by weight or more and 5.5 times by weight with respect to the rubber-based pressure-sensitive adhesive. The weight is not more than twice the weight, and more preferably not less than 2.6 times and not more than 5.0 times.

In one example of the present invention, the lower limit of the liquid paraffin content relative to the total amount of the pressure-sensitive adhesive component is preferably 30% by weight or more, more preferably 35% by weight or more, and most preferably It is 40% by weight or more. Further, the upper limit of the liquid paraffin content with respect to the total amount of the pressure-sensitive adhesive component is preferably 70% by weight or less, more preferably 65% by weight or less, and particularly preferably 60% by weight or less with respect to the total amount of the pressure-sensitive adhesive component. Yes, most preferably 55% by weight or less.

In one example of the present invention, the liquid paraffin content relative to the total amount of the pressure-sensitive adhesive component is preferably 30% by weight to 65% by weight, more preferably 35% by weight to 60% by weight, and most preferably 40%. % By weight or more and 55% by weight or less.

When the rubber adhesive is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer, the weight of liquid paraffin relative to the weight of the rubber adhesive is y, and the styrene-isoprene-styrene block. When the weight% of the styrene-isoprene-styrene copolymer in the mixture of the copolymer and the styrene-isoprene block copolymer is x and the base of the natural logarithm is e, 0.48e ^{0.022x -0.4≤y} ≦ e ^0.021x +0.4 is preferably represented by an exponential function, more preferably 0.48e ^0.022x −0.2 ≦ y ≦ e ^0.021x +0.2. More preferably, it is represented by an exponential function of 48e ^0.022x ≦ y ≦ e ^0.021x .
The patches of Examples 1 to 17 described later satisfy an exponential function of 0.48e ^0.022x ≤ y ≤ e ^0.021x .

(D) Tackifier A tackifier may be added to the pressure-sensitive adhesive layer. “Tackifier” is a tackifier that is generally used in the field of patches. For example, rosin resin, polyterpene resin, coumarone-indene resin, petroleum resin, terpene-phenol resin, alicyclic saturation A hydrocarbon resin etc. are mentioned. Since the release of the drug decreases when a large amount of the tackifier is added, the content of the tackifier is preferably 10% by weight or less, more preferably 5% by weight or less, more preferably 5% by weight or less. Most preferably not.

(E) Other components In the patch of the present invention, as necessary, (e1) surfactant, (e2) esters, (e3) alcohols, (e4) antioxidant, (e5) filler, etc. Can be included.

(E1) Surfactant Examples of the surfactant include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants.

Nonionic surfactants include, for example, sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquioleate, glycerol monooleate, glycerol monostearate, decaglyceryl monolaurate, hexaglycerin polyricinoleate, polyoxyethylene (9) Lauryl ether, polyoxyethylene (2) lauryl ether, polyoxyethylene (4,2) lauryl ether, polyoxyethylene (5) nonylphenyl ether, polyoxyethylene (7,5) nonylphenyl ether, polyoxy Ethylene (10) nonylphenyl ether, polyoxyethylene (3) octylphenyl ether, polyoxyethylene (10) octylphenyl ether, polyoxyethylene (10) oleylamine, Riokishi (5) oleylamine, polyoxy (5) oleic acid amide, polyoxyethylene (2) monolaurate, monoglyceride stearate, polyoxyethylene castor oil (hardened castor oil), and the like.

Examples of the anionic surfactant include sodium lauryl sulfate, potassium lauryl sulfate, triethanolamine lauryl sulfate, sodium cetyl sulfate, sodium lauroyl sarcosine, di-2-ethylhexyl sodium sulfosuccinate, polyoxyethylene (10) lauryl ether phosphorus Examples thereof include sodium acid, polyoxyethylene (4) sodium lauryl ether phosphate, polyoxyethylene (5) sodium cetyl ether phosphate, polyoxyethylene (6) sodium ether oil phosphate and the like.

Examples of the cationic surfactant include stearyl trimethyl ammonium chloride, distearyl dimethyl ammonium chloride, benzalkonium chloride, stearyl dimethyl benzyl ammonium chloride and the like.

Examples of the amphoteric surfactant include lauryldimethylaminoacetic acid betaine, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, and the like. In addition to the above, lauroyl diethanolamide can also be used. Among these, nonionic surfactants are preferable, and sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquioleate, glycerol monooleate, and glycerol monostearate are more preferable.

Surfactants may be used alone or in combination of two or more.

The content of the surfactant is not particularly limited, and the surfactant can be contained within a range in which high skin permeability and sufficient cohesive force and adhesive strength as a patch can be maintained. Preferably it is 5 weight% or less with respect to the adhesive agent whole quantity, More preferably, it is 3 weight% or less.

When a surfactant is used, it can be replaced with a rubber adhesive and / or liquid paraffin constituting the adhesive layer.

(E2) Esters Examples of the esters include isopropyl isostearate, methyl stearate, butyl stearate, butyl myristate, ethyl linoleate, isopropyl linoleate, ethyl olive oleate, myristyl myristate, cetyl isoctanate, myristine Fatty acids such as octyldodecyl acid, diisopropyl adipate, cetyl palmitate, retinol palmitate, methyl laurate, methyl myristate, methyl caproate, methyl palmitate, isopropyl myristate, isopropyl palmitate, diethyl sebacate, diethyl adipate Monohydric alcohol esters such as glyceryl monooleate, glyceryl monocaprate, glyceryl dioleate, propylene glycol monostearate And fatty acid polyhydric alcohol esters such as decaoleic acid decaglycerol, for example, fatty acid cyclic polyhydric alcohol esters such as sorbitan monostearate, sorbitan monolaurate, sorbitan monooleate, sorbitan trioleate, ascorbyl palmitate, such as lactic acid Lactic acid esters such as cetyl and myristyl lactate, carbonate esters such as propylene carbonate, and pyrrolidone derivatives such as N-methyl-2-pyrrolidone.

Esters may be used alone or in combination of two or more.
The ester content is not particularly limited, and the ester can be contained in a range where high skin permeability and sufficient cohesive force and adhesive strength can be maintained as a patch. Among these, the amount is preferably 55% by weight or less, more preferably 45% by weight or less, still more preferably 35% by weight or less, particularly preferably 25% by weight or less, and most preferably 15% by weight or less based on the total amount of the pressure-sensitive adhesive component. % By weight or less.

When esters are used, they can be substituted for the rubber-based pressure-sensitive adhesive and / or liquid paraffin constituting the pressure-sensitive adhesive layer. From the viewpoint of ensuring the cohesiveness of the preparation, it is preferable to replace it with liquid paraffin. All of the liquid paraffin may be replaced with esters, or a part thereof may be replaced.

(E3) Alcohols Examples of alcohols include aliphatic alcohols such as ethanol, isopropanol, lauryl alcohol, 2-octyldodecanol, 2-hexyldecanol, ethylene glycol, propylene glycol, 1,3-butanediol, and glycerin, such as salicylic acid. Aromatic alcohols such as glycol and benzyl alcohol can be mentioned. Preferred are aliphatic alcohols, and more preferred are lauryl alcohol, 2-octyldodecanol, 2-hexyldecanol, propylene glycol, 1,3-butanediol and the like. Alcohols may be used alone or in combination of two or more.

The content of alcohols is not particularly limited, and can be contained within a range in which high skin permeability and sufficient cohesive force and adhesive strength as a patch can be maintained. Among these, the amount is preferably 55% by weight or less, more preferably 45% by weight or less, still more preferably 35% by weight or less, particularly preferably 25% by weight or less, and most preferably 15% by weight or less based on the total amount of the pressure-sensitive adhesive component. % By weight or less.

When alcohols are used, they can be substituted for the rubber-based pressure-sensitive adhesive and / or liquid paraffin constituting the pressure-sensitive adhesive layer. From the viewpoint of ensuring the cohesiveness of the preparation, it is preferable to replace it with liquid paraffin. All of the liquid paraffin may be replaced with alcohols, or a part thereof may be replaced.

(E4) Antioxidant Examples of the antioxidant include dibutylhydroxyl toluene, 4-dioxyphenol, EDTA-2Na and the like. Of these, dibutylhydroxyl toluene is preferable. Antioxidants may be used alone or in admixture of two or more.

The content of the antioxidant is not particularly limited, and can be contained within a range where high skin permeability and sufficient cohesive force and adhesive strength can be maintained as a patch. Among these, the amount is preferably 10% by weight or less, more preferably 5% by weight or less, and most preferably 2% by weight or less based on the total amount of the pressure-sensitive adhesive component.

When an antioxidant is used, it can be replaced with a rubber-based pressure-sensitive adhesive and / or liquid paraffin constituting the pressure-sensitive adhesive layer.

(E5) Filler In order to control the softness | flexibility of an adhesive layer, a filler can be contained.
Examples of the filler include kaolin, titanium oxide, talc, calcium carbonate, magnesium carbonate, silicate, silicic acid, aluminum hydrate, barium sulfate, and calcium sulfate. The fillers may be used alone or in combination of two or more.

The content of the filler is not particularly limited, and can be contained within a range where high skin permeability and sufficient cohesive force and adhesive strength as a patch can be maintained. Among them, the amount is preferably 10% by weight or less, more preferably 5% by weight or less, and most preferably 2% by weight or less based on the total amount of the pressure-sensitive adhesive component.

When using a filler, it can be replaced with a rubber-based adhesive and / or liquid paraffin constituting the adhesive layer.

[Support]
The support used in the present invention is not particularly limited, and those generally used can be used. For example, polyester films, polyethylene films, polypropylene films, polyvinyl chloride films, polycarbonate films, polyurethane films and cellophane films and other non-woven fabrics, woven fabrics and knitted fabrics made of foam, polyester fibers, polyethylene fibers, polypropylene fibers, etc. And fabric bases such as these, and laminates thereof. Among these, a support made of a polyester material is preferable. Nonwoven fabrics, woven fabrics, and knitted fabrics are preferable in terms of stretchability, and transparent films are preferable in terms of usability.

[Method for preparing pressure-sensitive adhesive composition used in the manufacture of patch]
The patch of the present invention can be prepared using the pressure-sensitive adhesive composition described below. The pressure-sensitive adhesive composition can be prepared by mixing and stirring the components of the pressure-sensitive adhesive. That is, a pressure-sensitive adhesive composition can be obtained by mixing and stirring (a) lidocaine and other local anesthetics, (b) a rubber-based pressure-sensitive adhesive, and (c) liquid paraffin. For example, (a) to (c) may be sequentially added, or (b) and (c) may be mixed in advance, and then (a) may be mixed.

It is preferable to heat at the time of mixing and stirring because it is easy to mix uniformly. The heating temperature is preferably 50 ° C. or higher, more preferably 70 ° C. or higher, and most preferably 90 ° C. or higher. In order to prevent deterioration and volatilization of the components of the pressure-sensitive adhesive composition, the upper limit of the temperature is preferably 170 ° C. or lower, and more preferably 150 ° C. or lower.

Of these, the heating temperature is preferably 40 ° C. or higher and 170 ° C. or lower, more preferably 70 ° C. or higher and 170 ° C. or lower, particularly preferably 70 ° C. or higher and 150 ° C. or lower, and most preferably 90 ° C. or higher and 150 ° C. or lower. It is as follows.

Further, a solvent can be further added to the pressure-sensitive adhesive component to prepare a pressure-sensitive adhesive solution, which can be used for preparation of a patch.

The solvent that can be used in the present invention is not particularly limited as long as it can dissolve the adhesive component, but toluene, hexane, heptane, ethyl acetate, isopropyl acetate, n-propyl acetate and N-methyl- An organic solvent such as 2-pyrrolidone can be preferably used. In view of solubility and easy drying, toluene, hexane, heptane, ethyl acetate, and isopropyl acetate can be preferably used, and toluene is particularly preferable.

When a solvent is used during mixing and stirring, uniform mixing can be performed without any particular heating, but heating may be performed in order to achieve uniform and rapid mixing. The heating temperature is preferably 30 ° C or higher, more preferably 40 ° C or higher. If the temperature is too high, the solvent tends to volatilize, and therefore, the temperature is preferably 120 ° C. or lower, more preferably 100 ° C. or lower, and most preferably 90 ° C. or lower.

The heating temperature is preferably 30 ° C. or higher and 120 ° C. or lower among the above, more preferably 40 ° C. or higher and 100 ° C. or lower, and most preferably 40 ° C. or higher and 90 ° C. or lower.

[Preparation method of patch]
As a method for producing the patch of the present invention, a method of coating the pressure-sensitive adhesive layer on a support can be suitably used.

As a method for producing the patch of the present invention, a method similar to that of the pressure-sensitive adhesive tape can be employed. For example, a hot-melt coating method in which the pressure-sensitive adhesive composition is heated and melted and coated on a support, or a pressure-sensitive adhesive composition. Examples thereof include a solvent coating method in which a pressure-sensitive adhesive solution obtained by dissolving a product in an organic solvent is coated on a support and dried.

In addition, as a method for producing the patch of the present invention, the pressure-sensitive adhesive composition is once coated on the release paper, and then peeled off from the release paper and transferred and adhered to the support, or the coated surface without peeling is supported on the support. It is also possible to use a method of transferring and adhering to the substrate.

The release paper is used for the purpose of protecting the pressure-sensitive adhesive layer, and can be appropriately selected according to the purpose in consideration of easy release from the pressure-sensitive adhesive layer, air permeability, water permeability and flexibility. Preferably, a film made of a polymer material such as polyethylene, polypropylene and polyester is used, and the film surface can be treated with silicon or fluorocarbon in order to enhance the peelability.

In the patch of the present invention, the pressure-sensitive adhesive layer may be a single layer or a multilayer of two or more layers. In the case of a multilayer, at least one layer contains a mixture of lidocaine and other local anesthetics. It only has to be.

In the patch of the present invention, the thickness of the pressure-sensitive adhesive layer is preferably 20 μm or more and 2000 μm or less, more preferably 50 μm or more and 1500 μm or less, particularly preferably 100 μm or more and 1000 μm or less, and most preferably 120 μm or more and 600 μm or less. .

[Use of patch]
The patch of the present invention can be used as a transdermally absorbable preparation.
Since the patch of the present invention contains lidocaine and other local anesthetics, it can be used as a local anesthetic.
Further, since the patch of the present invention contains lidocaine and other local anesthetics, it can also be used as an analgesic or pain therapeutic agent, preferably as a neuropathic pain therapeutic agent, for example, It can be used as a therapeutic agent for neuralgia after herpes zoster.

Hereinafter, the present invention will be described more specifically with reference to examples and test examples, but the present invention is not limited to these examples. In addition, the numerical value of each component in Table 1 to Table 9 indicates parts by mass.

(Evaluation method) Evaluation of skin permeability The abdomen extracted skin of a male Wister rat (5 weeks old) from which hair was removed was attached to a vertical Franz diffusion cell (manufactured by Beadrex, model number: TP-8s). The patch prepared in the comparative example was punched into a circle having a diameter of 1.3 cm and stuck on the rat skin of a Franz diffusion cell. The test was conducted at a buffer temperature of 32 ° C. using 0.01 mol / L phosphate buffered saline (pH 7.2 to 7.4) containing 5% ethanol as a buffer. One hour after the start of the test, a part of the buffer was extracted, and the amounts of lidocaine and prilocaine that permeated the rat skin in the buffer were quantified by HPLC. The total permeation amount of lidocaine and prilocaine is defined as the permeation amount of drug. How many times the permeation amount of the drug when using the existing lidocaine patch (manufactured by Yutoku Yakuhin Kogyo Co., Ltd., product name: Yupatch (R) tape) The amount was evaluated.

(Evaluation method) Cohesive force The cohesive force of the patch was evaluated from the following viewpoints.
○: No adhesive residue was observed.
Δ: Slightly insufficient cohesion, but no problem.
X: Adhesive residue, loss of shape, etc. were observed, and lack of cohesive strength was remarkable.

(Evaluation method) Adhesiveness The adhesiveness of the patch was evaluated from the following viewpoints.
○: High adhesiveness compared to the existing local anesthetic patch (lidocaine tape).
Δ: Adhesiveness slightly lower than that of the existing local anesthetic patch (lidocaine tape).
X: Peeling was remarkable.

Example 1
5.40 g of a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene copolymer (styrene-isoprene-styrene block copolymer / styrene-isoprene copolymer weight mixing ratio = 50/50), After 8.45 g of toluene was added to 8.10 g of liquid paraffin and mixed, the mixture was heated and stirred at an internal temperature of 50 ° C. for 120 minutes for complete dissolution, and then cooled to 20-30 ° C. Next, 0.75 g of lidocaine and 0.75 g of prilocaine were sequentially added and mixed and stirred at the same temperature for 15 hours or more to obtain a uniform pressure-sensitive adhesive solution. The pressure-sensitive adhesive solution was applied to an 80 μm-thick polyethylene terephthalate (PET) film whose surface was silicon-treated using an applicator, and toluene was removed by drying in a hot air oven at 60 ° C. for 120 minutes or more. After forming an adhesive layer having a thickness of ˜450 μm, a PET film having a thickness of 60 μm was laminated on the surface of the adhesive layer to prepare a desired patch (transdermal absorption preparation). The components of the adhesive and the weight ratio (%) are shown in Table 1.

(Examples 2 and 3)
A patch was prepared in the same manner as in Example 1 except that lidocaine, prilocaine, SIS copolymer, and liquid paraffin were mixed at the ratio shown in Table 1.

Example 4
1.60 g of styrene-isoprene-styrene block copolymer (weight mixing ratio of styrene-isoprene-styrene block copolymer / styrene-isoprene copolymer = 50/50) and 1.60 g of liquid paraffin After 24 g of toluene was added and mixed, the mixture was heated and stirred at an internal temperature of 50 ° C. for 120 minutes for complete dissolution, and then cooled to 20 to 30 ° C. Next, 0.40 g of a tackifier, 0.20 g of lidocaine and 0.20 g of prilocaine were sequentially added and mixed and stirred at the same temperature for 15 hours or more to obtain a uniform adhesive solution. The pressure-sensitive adhesive solution was applied to an 80 μm-thick polyethylene terephthalate (PET) film whose surface was silicon-treated using an applicator, and toluene was removed by drying in a hot air oven at 60 ° C. for 120 minutes or more. After forming an adhesive layer having a thickness of ˜450 μm, a PET film having a thickness of 60 μm was laminated on the surface of the adhesive layer to prepare a target patch. The components of the adhesive and the weight ratio (%) are shown in Table 1.

(SIS)
SIS-A: Weight mixing ratio of styrene-isoprene-styrene block copolymer / styrene-isoprene copolymer = 80/20
SIS-B: Weight mixing ratio of styrene-isoprene-styrene block copolymer / styrene-isoprene copolymer = 50/50
SIS-C: Weight mixing ratio of styrene-isoprene-styrene block copolymer / styrene-isoprene copolymer = 22/78
SIS-D: Weight mixing ratio of styrene-isoprene-styrene block copolymer / styrene-isoprene copolymer = 88/12
SIS-E: Weight mixing ratio of styrene-isoprene-styrene block copolymer / styrene-isoprene copolymer = 74/26

All of the patches of Examples 1 to 4 showed good cohesive strength and adhesiveness. The skin permeability of the patches of Examples 1 to 4 was extremely high, 3.4 to 8.6 times the skin permeability of the existing lidocaine tape.

(Comparative Examples 1 to 6)
A patch was prepared in the same manner as in Example 1 except that lidocaine, SIS copolymer, and liquid paraffin were mixed at the ratio shown in Table 2.

When Lidocaine alone or Prilocaine alone were formulated as drugs, the patches of Comparative Examples 1 to 6 had low adhesiveness and were not at a practical level as pharmaceuticals.

(Comparative Examples 7 and 8)
A patch was prepared in the same manner as in Example 4 except that lidocaine, prilocaine, SIS copolymer and liquid paraffin were mixed at the ratio shown in Table 3.

The patches of Comparative Examples 7 and 8 had very good adhesive strength and cohesive strength due to the addition of the tackifier, but the drug did not have sufficient skin permeability compared to Examples 1 to 4.

(Comparative Example 9)
To 7.76 g of a cross-linked acrylic copolymer (Durotak 87-901A, 44 wt% solution), 0.20 g of lidocaine and 0.20 g of prilocaine were sequentially added and mixed and stirred at room temperature for 15 hours. An adhesive solution was obtained. The pressure-sensitive adhesive solution was applied to an 80 μm-thick polyethylene terephthalate (PET) film whose surface was silicon-treated using an applicator, and toluene was removed by drying in a hot air oven at 60 ° C. for 120 minutes or more. After forming an adhesive layer having a thickness of ˜450 μm, a PET film having a thickness of 60 μm was laminated on the surface of the adhesive layer to prepare a target patch. The components of the pressure-sensitive adhesive and the weight ratio (%) are shown in Table 4.

For the patch of Comparative Example 9 using an acrylic adhesive base, although the cohesive force and adhesive force were good, the skin permeability was significantly reduced as compared with Examples 1 to 4.

(Examples 5 and 6)
A patch was prepared in the same manner as in Example 1 except that lidocaine, prilocaine, SIS copolymer, and liquid paraffin were mixed in the types and ratios shown in Table 5.

The patches of Examples 5 and 6 in which the concentration of the drug was changed showed cohesive force and adhesiveness that had no practical problems, and had sufficiently high skin permeability.

(Examples 7 to 17)
A patch was prepared in the same manner as in Example 1 except that lidocaine, prilocaine, SIS copolymer, and liquid paraffin were mixed in the types and ratios shown in Table 6.

The patches of Examples 7 to 17 in which the ratio of the liquid paraffin to the SIS copolymer and the type of the SIS copolymer were changed exhibited cohesive force and adhesiveness that had no practical problems, and had sufficiently high skin permeability.

(Examples 18 and 19)
A patch was prepared in the same manner as in Example 1 except that lidocaine, prilocaine, SIS copolymer, and liquid paraffin were mixed in the types and ratios shown in Table 7.

The patches of Examples 18 and 19 in which the ratio of the liquid paraffin to the SIS copolymer and the type of the SIS copolymer were changed exhibited cohesive force and adhesiveness that had no practical problems, and had sufficiently high skin permeability.

(Examples 20 and 21)
A patch was prepared in the same manner as in Example 1 except that the drug substance, SIS copolymer, and liquid paraffin were mixed in the types and ratios shown in Table 8.

The patches of Examples 20 and 21 in which the type of the drug substance was changed showed cohesive strength and adhesiveness that had no practical problems, and had sufficiently high skin permeability.

(Examples 22 and 23)
A patch was prepared in the same manner as in Example 1 except that the drug substance, SIS copolymer, and liquid paraffin were mixed in the types and ratios shown in Table 9.

The patches of Examples 22 and 23 in which the mixing ratio of the drug substance was changed showed good cohesive strength and adhesiveness and sufficiently high skin permeability.

[Effects of analgesia or pain treatment]
(Test Example 1) Evaluation of in vitro rat skin permeability The patch prepared in Example 2 and the existing lidocaine patch Liderderm (manufactured by Teikoku Pharmaceutical Co., Ltd.) were punched into a circle with a diameter of 1.3 cm, and HWY / Slc It was affixed on the abdominal extract skin of a male male hairless rat (5 weeks old). The skin was set in a vertical diffusion cell, and the test was started with a transdermal absorption test automatic sampling device (manufactured by Cosmedy). 0.01 mol / L phosphate buffered saline (pH 7.2 to 7.4) was used as a buffer, and the buffer temperature was 32 ° C. 3, 6, 9, 12, 18, and 24 hours after the start of the test, a part of the buffer was extracted, and the amount of lidocaine and prilocaine that permeated the rat skin in the buffer was quantified by HPLC. The sum of the permeation amounts of lidocaine and prilocaine was used as the drug permeation amount, and the number of permeation amounts with respect to the drug permeation amount when Lidoderm was used was evaluated. The measurement result of the cumulative drug skin permeation amount is shown in FIG. 1, and the measurement result of the drug skin permeation rate is shown in FIG.

(Test Example 2) Evaluation of analgesic action in rat Chung model The analgesic action was evaluated using the Chung model which is a neuropathic pain model. The rat Chung model was prepared according to the method of Kim and Chung (Pain 50 (3), 355-363 (1992)). Specifically, 6-week-old Crl: CD (SD) male rats (8 rats per group) were used to expose the L5 and L6 spinal nerves under isoflurane anesthesia, and the central side was silk thread (5-0). ) Strongly ligated. After suturing the wound and raising it for 1 week, using Lidoderm, an existing lidocaine patch as a control formulation, and the pain threshold of the patch of Example 2 as a test substance, using a dynamic planter esthetic ratio meter (manufactured by Ugobasil) It was measured. The patch was affixed to the sole of the left limb for 12 hours, and the measurement time was immediately after the preparation was peeled off (0 hour) and after 2 hours. The pain threshold value is expressed as an average value ± standard error for each group, and the test results are shown in Table 10. The significant difference test was performed using Dunnett's multiple comparison test in the multi-group comparison between the Lidoderm-administered group and the Example 2 formulation-administered group, and P <0.05 was considered significant (see Table 10). * P <0.05).

When the analgesic action was evaluated, the pain threshold value of the patch application group of Example 2 was significantly higher than that of the Lidoderm administration group immediately after peeling the patch for 12 hours and after 2 hours of peeling. Furthermore, it was revealed that the analgesic action lasts for a longer time than Lidoderm. That is, in the treatment of postherpetic neuralgia, the patch of the present invention has a significantly higher therapeutic effect than Lidoderm, and thus is useful as a preparation for treating superficial and localized neuropathic pain. I understood that.

Claims (28)

A patch formed from an adhesive layer containing 5% by weight or more and less than 20% by weight of a mixture of lidocaine and another local anesthetic, wherein the adhesive layer contains at least a rubber adhesive and liquid paraffin; And the patch whose content of the tackifier in the said adhesion layer is 10 weight% or less. The patch according to claim 1, wherein the liquid paraffin is 0.5 to 2.6 times the weight of the rubber-based adhesive. The patch according to claim 1, wherein the liquid paraffin is 0.6 to 2.0 times by weight with respect to the rubber-based adhesive. The patch according to claim 1, wherein the liquid paraffin is 0.7 to 1.5 times the weight of the rubber adhesive. The patch according to any one of claims 1 to 4, wherein the rubber adhesive is a styrene block copolymer. The patch according to claim 5, wherein the rubber-based adhesive is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer. The patch according to claim 6, wherein the content of the styrene-isoprene-styrene copolymer in the mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer is 15 wt% or more and 60 wt% or less. . The patch according to claim 6, wherein the content of the styrene-isoprene-styrene copolymer in the mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer is 20 wt% or more and 50 wt% or less. . The patch according to claim 1, wherein the liquid paraffin is 2.0 to 6.0 times by weight with respect to the rubber adhesive. The patch according to claim 1, wherein the liquid paraffin is 2.3 to 5.5 times by weight with respect to the rubber adhesive. The patch according to claim 1, wherein the liquid paraffin is 2.6 to 5.0 times by weight with respect to the rubber-based adhesive. The patch according to any one of claims 9 to 11, wherein the rubber adhesive is a styrene block copolymer. The patch according to claim 12, wherein the rubber-based adhesive is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer. The patch according to claim 13, wherein the content of the styrene-isoprene-styrene copolymer in the mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer is 60 wt% or more and 95 wt% or less. . The patch according to claim 13, wherein the content of the styrene-isoprene-styrene copolymer in the mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer is 70% by weight or more and 90% by weight or less. . The rubber adhesive is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer, the weight of liquid paraffin relative to the weight of the rubber adhesive is y, and the styrene-isoprene-styrene block copolymer. When the weight% of the styrene-isoprene-styrene copolymer in the mixture of styrene and isoprene block copolymer is x and the base of the natural logarithm is e, 0.48e ^0.022x -0.4 ≦ y ≦ e ^0.021 The patch according to claim 1, which is represented by an exponential function of ^x +0.4. The rubber adhesive is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer, the weight of liquid paraffin relative to the weight of the rubber adhesive is y, and the styrene-isoprene-styrene block copolymer. When the weight% of the styrene-isoprene-styrene copolymer in the mixture of styrene-isoprene block copolymer is x and the base of the natural logarithm is e, 0.48e ^{0.022x -0.2≤y≤e 0.021} The patch according to claim 1, which is represented by an exponential function of ^x +0.2. The rubber adhesive is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer, the weight of liquid paraffin relative to the weight of the rubber adhesive is y, and the styrene-isoprene-styrene block copolymer. Exponential function of 0.48e ^0.022x ≤ y ≤ e ^0.021x , where x is the weight percent of the styrene-isoprene-styrene copolymer in the mixture of styrene-isoprene block copolymer and e is the base of the natural logarithm The patch of Claim 1 represented by these. The patch according to any one of claims 1 to 18, wherein the other local anesthetic is prilocaine, tetracaine or benzocaine. The patch according to claim 19, wherein the lidocaine content in the mixture of lidocaine and another local anesthetic is 30% by weight or more and 70% by weight or less. The patch according to claim 19, wherein the lidocaine content in the mixture of lidocaine and another local anesthetic is 40 wt% or more and 60 wt% or less. The patch according to claim 19, wherein the lidocaine content in the mixture of lidocaine and another local anesthetic is 45 wt% or more and 55 wt% or less. The patch according to claim 19, wherein the weight ratio of the mixture of lidocaine and another local anesthetic is 50/50. The patch according to any one of claims 19 to 23, wherein a content of the mixture of lidocaine and another local anesthetic is 5% by weight or more and less than 15% by weight with respect to the total amount of the adhesive component. The patch according to any one of claims 1 to 24, wherein the adhesive layer does not contain a tackifier. The patch according to any one of claims 1 to 25, which is used as a local anesthetic. The patch according to any one of claims 1 to 26, which is used as an analgesic or a pain treatment agent. The patch according to claim 27, which is used as a therapeutic agent for neuropathic pain.

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